As a newly appointed professor in cardiovascular endocrinology, one gets to speculate on what cardiovascular endocrinology actually entails. Clearly, the term gets its wordy justification from two established medical disciplines (e.g. cardiology and endocrinology). Combining the two, however, contains more than just the mutual interest in, for instance, diabetes mellitus and its complications that, nowadays, are dominantly cardiovascular. Cardiovascular endocrinology must look beyond established hormonal axes for new ways of thinking, and this search should not be confined to identifying new markers of disease nor treatment strategies but help elucidate entirely new mechanisms that link the cardiovascular system with the plethora of blood-borne bioactive substances and their referred cellular targets.
Cardiovascular endocrinology must appreciate earlier pioneers in the field. In my view, Ernest Henry Starling may be considered ‘the father’ of the discipline as he, together with William Maddock Bayliss, first described the existence of blood-borne substances with independent cellular actions 1. By demonstrating the physiological effects of duodenum-extracted secretin on pancreatic exocrine secretion, endocrinology was introduced as an independent medical discipline and represented an equal regulatory system to the prevailing paradigm of only nervous intercellular communication in that time 2. Starling moved on with his research activities and later described the contractile law of the heart 3. The pumping function of the heart could now help explain how the heart integrally regulates its own output as a relative function of input. Taking these milestone findings together, the basics for undertaking cardiovascular endocrinology were thus possible almost 100 years ago. Notably, Starling never received a Nobel Prize for his multifaceted work, a fact that still puzzles (and troubles) great scientists 4.
A second aspect of cardiovascular endocrinology involves the modern treatment of hypertension, cardiac arrhythmias, ischemic heart disease, and congestive heart failure by blocking or enhancing different hormonal systems. The clinical use of angiotensin-converting-enzyme inhibition or receptor blocking is now almost as commonly recommended as vitamin supplements and fish oils. Moreover, adrenergic receptor blockade constitutes a cornerstone in hypertension, cardiac arrhythmias and heart failure, and aldosterone inhibition is also an important supplement in heart failure treatment. Thus, when the heart does not fulfill its overall hemodynamic functions, neurohumoral activation takes over, usually with dire consequences for the suffering heart muscle. Clinicians must then intervene with treatment that lower morbidity and mortality using drugs targeted at endocrine axes. Thus, cardiovascular endocrinology has for a long time been applied in the modern medical treatment of cardiovascular patients, and the search for new enhancing or blocking ‘endocrine’ drugs is surely underway.
The central organ in the cardiovascular system is the heart itself. Cardiac myocytes produce and release natriuretic peptides with potent effects on renal sodium excretion, blood pressure and vascular permeability 5. Atrial and B-type natriuretic peptides are also plasma markers of heart disease, and measurement of the bioactive peptides, or their precursor fragments, is recommended in heart failure diagnostics 6. Initially, the cardiomyocytes were believed to be fairly inefficient hormone-producing cells with little biosynthetic capacity. However, the heart cells are now known to be highly specialized endocrine cells with complex and elaborate post-translational processing 7. In perspective, it may therefore be worthwhile to look for other regulatory peptides produced in the heart, as endocrine cells often harbor more than one bioactive substance. One such substance has been suggested to be apelin, a small potent peptide with isotropic effects, which is otherwise produced in the stomach and the vasculature. The precise role for cardiovascular apelin clearly remains of potential interest, both as therapy and as a biomarker 8. Another potential cardiac-derived peptide is relaxin, although the precise role of this local expression is still unresolved 9.
In the darkness of the bowel resides the largest endocrine system in the human body. With more than 100 known bioactive substances, the endocrine gut is involved in almost every physiological mechanism. From a cardiovascular point of view, most attention has been paid to insulin and later the incretins (which facilitate insulin release). In fact, insulin infusion used to be considered a reasonable treatment of acute myocardial infarction, and the days of glucose–insulin–potassium infusion are not completely over 10. The cardiac myocytes express receptors for both insulin and glucagon, and thus they also affect cardiac metabolism and function. Interestingly, both peptides seem to possess independent cardioprotective properties, that is they protect cardiomyocytes from apoptosis under different forms of stress 11. This cardioprotective aspect will certainly be pursued in the near future, as the need for such adjuvant therapy is overwhelming. In the light of the present interest in incretin, it should not be overlooked that the gut still produces a large number of other bioactive peptides with potential effects on the cardiovascular system.
Finally, other hormonal axes are involved in cardiovascular function and disease. For decades, the pituitary vasopressin (an antidiuretic peptide) has been known to be involved in the heart failure syndrome. Recently, a method for measuring the stable C-terminal copeptin fragment from the vasopressin precursor was introduced and a new marker in heart failure was established 12. Chromogranins are another example of new possible players in cardiovascular disease, where chromogranin A concentrations in plasma are associated with mortality after infarction 13, and chromogranin A and chromogranin B even seem to be produced in the heart itself 14,15. Last, but not the least, adipokines such as leptin 16 and adiponectin 17 also seem to be important players in cardiovascular disease.
So have I defined cardiovascular endocrinology? Clearly, it is not a simple and straightforward discipline. It involves almost all cells in the human organism, and the search for new hormonal axes and involvement in cardiovascular disease is still only in the early phase. It will therefore be important not to only focus on established mechanisms but also to look for new roles of ‘old hormones’; the work in doing so must combine researchers from several fields including ones that are not normally thought of in cardiovascular research. I believe that cardiovascular endocrinologists must possess a particular ability to collaborate with many different colleagues in order to maximize the vast potential in the field.
Let me end on a quote from Ernest Henry Starling, as it vividly captures his engagement and uncompromising personality. Modern cardiovascular endocrinology should seek for new mechanisms and links obeying these fundamental words for good research: Starling did so, and so must we.
‘Science has only one language, quantity, and only one argument, the experiment’.
The paper was supported by a grant from the Novo Foundation.
Conflicts of interest
There are no conflicts of interest.
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